Residing mostly in the bone marrow are pluripotent stem cells giving rise to various blood cells. Proliferation and differentiation of the blood cell progeny is regulated by a series of myleloid growth factors thought to be produced in stromal cells, also contained in the marrow microenvironment [N. S. Wolf, "The Hemopoietic Microenvironment", Hematol, 8, p. 469 (1979); D. Zipori, "Cultured Stromal Cell Lines From Hemopoietic Tissues". In: Blood Cell Formation ed. M. Tanassoli, Marcel Dekker, Inc. In Press]. These myleloid growth factors are labelled hematopoietic colony-stimulating factors, or CSF'S. Macrophage-CSF (M-CSF or CSF-1) stimulates the formation of monocytes/macrophages; granulocytemacrophage-CSF (GM-CSF) having a broad range of activity, stimulates the formation of neutrophils (or granulocytes), monocytes/macrophages, eosinophils, erythrocytes and megakaryocytes [P. H. Plusnik et al., J. Cell. Comp. Physiol., 66, p. 319 (1965); D. Metcalf, "The Hemopoietic Colony Stimulating Factors" (Elsevier, Amsterdam, 1984)]; and, multi-CSF (Interleukin 3 or IL3) stimulates the formation of neutrophils, monocytes/macrophages, eosinophils, megakaryocytes as well as basophils [P. Quesenberry et al., "The Effect of IL3 and GM-CSA-2 On Megakaryocytes and Myeloid Clonal Colony Formation", Blood, 65, p. 214 (1985)].
As a result of their biological properties GM-CSF, CSF-1 and IL3, may be used for various types of therapy requiring stimulation of the differentiation or proliferation of various hematopoietic lineages. For example, therapy with the growth factors given prior to, concommitantly with, or following chemotherapy or radiation, to increase or maintain blood count would be useful for cancer and autoimmune diseases. Bacterial, fungal or other infections could thus be obviated in these patients having a reduced level of neutrophilic granulocytes from the chemotherapy or radiotherapy. More specifically, GM-CSF and IL3 could be used as an adjuvant during bone marrow transplants, both for cancer and noncancer treatment, for example, thalassemia. Furthermore, GM-CSF and IL-3 can act as differentiation agents, beneficial in the treatment of bone marrow cell differentiation disorders such as leukemia. Also, they may be useful in the treatment of congenital and acquired aplastic anemias in which there is a deficiency of activated bone marrow stem cells.
Also derived from pluripotent stem cells are antigen responsive B lymphocytes ("pre-B cells"), the precursors of plasma cells which are highly specialized for antibody production and secretion. Briefly, antigens react with B cell surface bound antibodies to produce plasma cells. Little is known about regulatory events for pre-B cell development or components of the marrow microenvironment which may mediate pre-B cell differentiation.
Because of the important therapeutic potential of the growth factors GM-CSF, CSF-1 and IL3, and the importance of regulating the production of B cells, it would therefore be of interest to identify and isolate a hemolymphopoietic growth factor (HLGF-1) which augments the effect of or synergizes with GM-CSF, CSF, CSF-1 and IL3, while also being capable of potentiating pre-B cell production.
At present, compounds reported as displaying synergy with CSF-1 in supporting the proliferation of monocytes/macrophages include IL3 and hemopoietin-1 [E. R. Stanley et al., "Factors affecting The Growth And Differentiation Of Hemopoietic Cells In Culture", Clin. Haematal, 13, p. 329 (1984); S. H. Bartelmez et al., "Synergism Between Hemopoietic Growth Factor Detected By Their Effects On Cells Bearing Receptors For A Lineage Specific HGF: Assay Of Hemopoietin-1", J. Cell Physiol, 122, p. 370 (1985); I. McNiese et al., "Recombinant Interleukin-3 Exhibits Synergistic Factor Activity", Cell. Biol. Int. Rep., 8, p. 812 (1984)]. However, IL3 and hemopoietin-1 have not been demonstrated to also induce pre-B cell formation. Synergistic activity for giant macrophage colony formation has also been shown by combining pregnant uterus extract (as the colony stimulating factor) with human spleen-conditioned medium in nutrient agar cultures but without pre-B-inducing activity [T. R. Bradley, "Detection of Primitive Macrophage Progenitor Cells in Mouse Bone Marrow", Blood, 54, p. 1446 (1979)].